The present invention relates to triaryl compounds, particularly biphenyl pyridines, biphenyl benzamides and biphenyl phenylcarboxy compounds, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.
Specifically, the invention provides a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical, e.g. for use in the treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma.
In a further embodiment the invention provides a pharmaceutical composition comprising a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, e.g. in combination with a pharmaceutically acceptable diluent or carrier.
In a yet further embodiment the invention includes the use of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, for the preparation of a medicament for treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma.
In a still yet further embodiment the invention provides a method for treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma, comprising administering an effective amount of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, to a subject in need of such therapy.
The (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compounds of the invention and their pharmaceutically acceptable acid addition salt forms are hereinafter referred to as AGENTS OF THE INVENTION. In these compounds, the 4-oxy moiety is suitably (optionally fluoro-substituted)alkoxy, e.g., (fluoro0-3-)C1-4alkoxy, e.g. methyl, ethyl, difluoromethyl, or trifluoromethyl. The 3-aryl moiety is suitably a mono- or bicyclic moiety having at least one aromatic ring, e.g., azaryl, for example pyridyl, C1-4alkylpyridyl, or quinolinyl; aromatic 2,5-cyclohexadien-3,4-ylidine-1-yl, e.g., benzofurazanyl or benzofuranyl; or phenyl, preferably suitably substituted, e.g., meta- and/or para-substituted, with (i) one or two substitutents selected from nitro, carbamoyl, halo (e.g., chloro), trifluoromethyl, alkoxy (e.g. C1-4alkoxy), thioalkoxy (e.g. thio(C1-4)alkoxy), alkylsulphoxy (e.g. C1-4alkylsulphoxy), alkylsulphonyl (e.g. C1-4alkylsulphonyl), cyano, or phenoxy, or (ii) a bridging substituent of 3-5 atoms in length wherein the bridge atoms are selected from C, O, S, and N, e.g. indanyl, benzopyrolidonyl, indanonyl, or benzodioxolanyl. By xe2x80x9cazarylxe2x80x9d is meant a nitrogen-containing aromatic group, for example, pyridine, e.g., 3-pyridine or 4-pyridine, quinoline, isoquinoline, imidazopyridine (e.g. imidazo[1,2-a]pyridine or benzamide, e.g., 3- or 4-benzamide. By xe2x80x9carylcarbonyloxyxe2x80x9d is meant an aryl moiety, e.g. as defined above for the 3-aryl moiety, bearing at least one carbonyloxy substituent, e.g. in free acid, ester, amide or salt form, preferably a phenylcarboxy moiety, e.g. a phenyl-3- or phenyl-4-carboxy moiety, such as a phenyl carboxylic acid or phenyl carboxylate ester (e.g. lower alkyl phenyl carboxylate ester) or phenylcarboxamido moiety. Halo or halogen as used herein refers to F, Cl, Br or I unless otherwise indicated.
AGENTS OF THE INVENTION include compounds which are known per se but for which no pharmaceutical activity has been described or suggested. Thus Jin et al. (Macromol. Symp. ( 1995), 96 [International Conference on Liquid Crystal Polymers 1994], 125-134) describe methyl-4xe2x80x2-methoxy-3xe2x80x2-phenylbiphenyl-4-carboxylate and 4xe2x80x2-acetoxy-3xe2x80x2-phenylbiphenyl-4-carboxylic acid as intermediates in the preparation of copolyester liquid crystal materials. Buu-Hoi et al. (J. Org. Chem. 21, [1956], 136-138) describe the preparation of 2-(6-methoxy-biphenyl-3yl)-quinoline and anolgues thereof further substituted in the quinoline ring by methyl or phenyl at position 3 and/or by carboxy at position 4, and (J. Org. Chem. 29, [1964], 762-763) also describe the preparation of 2-(6,2xe2x80x2-dimethoxy-biphenyl-3-yl)-quinoline, and analogues thereof further substituted in the quinoline ring by methyl at position 3 and/or by carboxy at position 4. Buu-Hoi et al. do not identify any utility or activity for these quinoline compounds. Du Pont Belgian patent 652,320 describes the preparation of 5-(6-methoxy-biphenyl-3-yl)-2-methyl thiazole as an intermediate in the preparation 5,5xe2x80x2-diphenylthiazolecarbocyanine sensitisers of silver halide emulsions for photographic use.
Accordingly the present invention provides a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, e.g. wherein the 4-oxy, 3-aryl, azaryl and arylcarbonyloxy moieties are as defined above, provided
that the 3-aryl moiety is not unsubstituted phenyl when
the arylcarbonyloxy moiety is phenyl-4-carboxylic acid or phenyl-4-methylcarboxylate, or
the azaryl moiety is 5-methylthiazol-2-yl, or
that the 3-aryl moiety is not unsubstituted phenyl or 2-methoxyphen-1-yl when
the azaryl moiety is unsubstituted 2-quinoline or 2-quinoline substituted by methyl or phenyl at position 3 and/or by carboxy at position 4,
or a pharmaceutically acceptable acid addition salts thereof.
The novel compounds of this aspect of the invention are encompassed by the AGENTS OF THE INVENTION.
The AGENTS OF THE INVENTION may exist in free form or in the form of pharmaceutically acceptable acid addition salts. Pharmaceutically active acid addition salts for use in the present invention include for example chlorhydrates, oxalates and fumarates.
In particular, the invention provides an AGENT OF THE INVENTION which is a 4-(oxy)-3-[phenyl or (2,5-cyclohexadien-3,4-ylidine-1-yl)]-phenyl-azaryl or -arylcarbonyloxy in free or pharmaceutically acceptable acid addition salt form. Optionally, the 3-phenyl moiety is substituted, e.g. 3- and/or 4-substituted. The 2,5-cyclohexadien-3,4-ylidine-1-yl moiety is preferably a 2,5-cyclohexadien-3,4-N-ylidine-1-yl moiety, preferably aromatic. Preferably, the oxy moiety is alkoxy, e.g. C1-4alkoxy. The azaryl moiety is preferably pyridine, e.g., 4-pyridine, imidazopyridine, e.g. 6-imidazo[1,2-a]pyridine, or benzamide, e.g., 3- or 4-benzamide. Preferably the arylcarbonyloxy moiety is phenylcarboxy, e.g. phenyl-3- or 4-carboxy. For example, the AGENTS OF THE INVENTION include a [2-(C1-4alkoxy)-biphenyl-5-yl]pyridine, [2-(C1-4alkoxy)-biphenyl-5-yl]benzamide or [2-(C1-4alkoxy)-biphenyl-5-yl]phenylcarboxy wherein the biphenyl moiety is optionally 3xe2x80x2- and/or 4xe2x80x2-substituted or optionally 3xe2x80x2,4xe2x80x2-fused to a second aromatic ring, preferably a compound of formula Ia or formula Ib: 
wherein
in formula Ia W is N or Cxe2x80x94COxe2x80x94R,
wherein R is OH, Oxe2x80x94(C1-6)alkyl or NR3R4 
wherein R3 and R4 which may be the same or different are H or (C1-6)alkyl, or
in formula Ib Az is an azaryl group containing one or more nitrogen atoms, such as quinoline, isoquiniline, indole, imidazopyridine, e.g. imidazo[1,2-a]pyridine,
and in both formula Ia and Ib
R1 is (C1-4)alkyl, preferably methyl; and
R2 is a phenyl moiety, e.g., of formula II 
wherein R5 and R6 are, independently, H, nitro, halo (e.g., chloro), trifluoromethyl, (C1-4)alkoxy, cyano, or phenoxy; or R5 and R6 together form a bridge of 3-5 atoms in length wherein the bridge atoms are selected from S, O, N, and C, e.g. xe2x80x94OCH2Oxe2x80x94, or propylene;
or R2 is a 2,5-cyclohexadien-3,4-ylidine-1-yl moiety, e.g., of formula III 
wherein R7 and R8 together form an aromatic bridge of 3-5 atoms in length wherein the bridge atoms are selected from S, O, N, and C, e.g., xe2x95x90Nxe2x80x94Oxe2x80x94Nxe2x95x90;
in free or pharmaceutically acceptable acid addition salt form.
Most preferably, R2 is selected from 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 3-cyanophenyl, 3- or 3,4-halophenyl (e.g., 3-chlorophenyl or 3-chloro-4-fluorophenyl), indan-5-yl, benzofurazan-5-yl, and 1,3-benzo[d]dioxolan-5-yl.
Compounds of formula I thus include:
1. 4-[2-(methoxy)-biphenyl-5-yl]pyridine
2. 4-[2-(methoxy)-3xe2x80x2-(nitro)biphenyl-5-yl]pyridine
3. 4-[2-(methoxy)-3xe2x80x2-(trifluoromethyl)biphenyl-5-yl]pyridine
4. 4-[2-(methoxy)-3xe2x80x2,4xe2x80x2-(propylene)biphenyl]pyridine
5. 4-[4-(methoxy)-3-(benzofurazan-5-yl)phenyl]pyridine
6. 4-[2-(methoxy)-3xe2x80x2-(cyano)biphenyl-5-yl]pyridine
7. 4-[2-(methoxy)-3xe2x80x2-(chloro)biphenyl-5-yl]pyridine
8. 4-[2-(methoxy)-3xe2x80x2,4xe2x80x2-(methylenedioxy)biphenyl-5-yl]pyridine
9. 4-[2-(methoxy)-3xe2x80x2-(phenoxy)biphenyl-5-yl]pyridine
10. 4-[2-(methoxy )-4xe2x80x2-(phenoxy)biphenyl-5-yl]pyridine
11. 4-[2-(Methoxy)-3xe2x80x2-(chloro)-4xe2x80x2-(fluoro)biphenyl-5-yl]pyridine
12. 4xe2x80x2-Methoxy-3xe2x80x2-(benzofurazan-5-yl)-[1,1xe2x80x2-biphenyl]-4-carboxamide
13. 4xe2x80x2-Methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxylic acid, ethyl ester
14. 4xe2x80x2-Methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-3-carboxylic acid, ethyl ester
15. 4xe2x80x2-Methoxy-3-methyl-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxylic acid, ethyl ester
16. 3xe2x80x2-(5-Benzofurazanyl)-4xe2x80x2-methoxy-[1,1xe2x80x2-biphenyl]-4-carboxylic acid, ethyl ester
17. 3xe2x80x2-(5-Benzofurazanyl)-4xe2x80x2-methoxy-[1,1xe2x80x2-biphenyl]-4-carboxylic acid, 2,2-dimethylpropyl ester
18. 3xe2x80x2-(5-Benzofurazanyl)-4xe2x80x2-methoxy-[1,1xe2x80x2-biphenyl]-4-carboxylic acid
19. 4xe2x80x2-Methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-3-carboxylic acid
20. 4xe2x80x2-Methoxy-3-methyl-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxylic acid
21. 3xe2x80x2-(5-Benzofurazanyl)-4xe2x80x2-methoxy-[1,1xe2x80x2-biphenyl]-4-carboxylic acid
22. 4xe2x80x2-Methoxy-3xe2x80x2-(3-chlorophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxylic acid
23. 4xe2x80x2-Methoxy-3xe2x80x2-(3-cyanophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxylic acid
24. 4xe2x80x2-Methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxamide
25. 4xe2x80x2-Methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-3-carboxamide
26. 4xe2x80x2-Methoxy-3-methyl-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxamide
27. N-Methyl-4xe2x80x2-methoxy-3xe2x80x2-(3-nitrophenyl)-[1,1xe2x80x2-biphenyl]-4-carboxamide
28. 6-[4-Methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine
in free or pharmaceutically acceptable acid addition, e.g., hydrochloride, salt form.
Compounds of formula I are suitably prepared by reacting a compound of formula Ixe2x80x2a or formula Ixe2x80x2b: 
wherein X is halogen(preferably bromine) or a leaving group, such as a tin or boron containing group (preferably xe2x80x94B(OH)2), and R1, W and Az are as defined above for formula Ia and Ib, with the desired activated aryl, e.g., aryl halide or aryl boronic acid, for example, a compound of formula IIa or IIIa: 
wherein Y is halogen (preferably bromine) or a leaving group, such as a tin or boron containing group (preferably xe2x80x94B(OH)2), and the R groups are as defined above for Formula II and III; and recovering the resulting compound of the invention, e.g., of formula Ia or Ib, in free or acid addition salt form. Preferably, one of X or Y is halogen, e.g. bromine, and the other is a leaving group, e.g., xe2x80x94B(OH)2. Suitable reaction conditions may include reaction in the presence of one or more of the following: a nucleophile such as triarylphosphine (preferably tri-o-tolylphosphine or tri-2-furylphosphine); a base such as sodium carbonate, a solvent such as toluene, acetonitrile, or DMF, and/or a suitable catalyst such as a palladium catalyst. Suitable reaction temperatures include from ambient temperature to the boiling point of the solvant, e.g., from 20-150xc2x0 C., preferably 70-90xc2x0 C.
Novel intermediates, especially of formula Ixe2x80x2a and Ixe2x80x2b, are comprised within the scope of the invention. Compounds of formula Ixe2x80x2a and Ixe2x80x2b can be prepared by a Suzuki- or Stille-type coupling reaction, for example between a 4-alkoxyboronic acid derivative and the suitably substituted haloaromatic system, or alternatively prepared from 4-halopyridine and the corresponding Grignard reagent e.g., by reacting 4-bromopyridine with a compound of formula R1Oxe2x80x94C6H4xe2x80x94MgBr wherein R1 is as defined above, in the presence of a suitable catalyst, e.g., a nickel catalyst, to obtain the 4-aryl-pyridine, which is then halogenated, e.g., by reaction with Br2, to obtain the compound of formula Ixe2x80x2a or Ixe2x80x2b where X is halogen, and optionally further reacting with one or more alkylmetal reagents, e.g., with alkyllithium, e.g., butyllithium, followed by reaction with alkylborate, e.g., triethylborate, to obtain the compound of formula Ixe2x80x2a or Ixe2x80x2b where X is xe2x80x94B(OH)2. Compounds of formula IIa or IIIa can be prepared analogously, by halogenation of the aryl, e.g., bromination, optionally followed by exchange of the halogen for a leaving group, e.g., xe2x80x94B(OH)2.